Elevated expression of Ubiquitin C-terminal Hydrolase L1 (UCH L1) has been observed and associated with a poor prognosis in a number of human malignancies, including B-cell lymphomas. Although the involvement of this deubiquitinating enzyme in oncogenesis has thus been suggested, verification is largely lacking, and physiological functions and regulation of UCH L1 in cancer cells are still mainly unknown. While the role of the ubiquitin/ proteasome system in cell oncogenic transformation is well etablished, the impact of deubiquitinating enzymes (DUBs) in this process is largely unexplored. Our recent studies show that Epstein-Bar Virus-dependent transformation of B-cells induces expression of Ubiquitin C-terminal Hydrolase L1 (UCH L1) in normal B- lymphocytes, and its deubiqutinating activity is involved in activation of oncogenic pathways. We propose to investigate whether expression and enzymatic activity of UCH L1 affects basic cellular functions such as proliferation, survival and migration in B-lymphoma cell lines. Understanding of these functional inputs will identify UCH L1 as a new player in cell cycle progression and a potential target for a broadly based therapeutic approach. PUBLIC HEALTH RELEVANCE: Closely involved in regulation of numerous signaling pathways in tumor cells, the ubiquitin system in the last several years has become an attractive target for anti-cancer therapy. Although some proteasome inhibitors are useful in treatment of a variety of malignancies by inducing apoptosis in cancer cells, targeting of other steps of the ubiquitin system, such as specific DUBs, might produce more selective effects, since ubiquitinating and deubiquitinating complexes specifically bind to potential substrates. Our preliminary results indicate that a small-molecule inhibitor of UCH L1 enzymatic activity inhibits trans-endothelial migration of B-lymphoma cells and therefore might have a potential anti-invasive effect on lymphoid cancers. The goal of this proposal is to obtain experimental data on UCH L1 physiological functions in transformed cells and potentially to validate the deubiquitinating enzyme UCH L1 as a diagnostic marker and a novel target for anti-cancer therapy in specific malignancies such as non-Hodgkins and certain Hodgkins lymphomas.